Compositions and methods for the treatment of irritable bowel syndrome

ABSTRACT

The disclosures herein provide compounds of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X, formula XI, formula XII, formula XIII, formula XIV and formula XV or its pharmaceutical acceptable salts, as well as polymorphs, enantiomers, stereoisomers, solvates, and hydrates thereof. These salts may be formulated as pharmaceutical compositions. The pharmaceutical compositions may be formulated for oral administration, suppository, transdermal, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of irritable bowel syndrome (IBS), inflammatory bowel diseases or its associated complications.

PRIORITY

The present application claims the benefit of Indian Provisional PatentApplication No. 201641027529 filed on 11 Aug. 2016, the entiredisclosure of which is relied on for all purposes and is incorporatedinto this application by reference.

FIELD OF THE INVENTION

This disclosure generally relates to compounds and compositions for thetreatment of irritable bowel syndrome (IBS). More particularly, thisinvention relates to treating subjects with a pharmaceuticallyacceptable dose of compounds, crystals, solvates, enantiomer,stereoisomer, esters, salts, hydrates, prodrugs, or mixtures thereof.

BACKGROUND OF THE INVENTION

Irritable bowel syndrome (IBS) is considered by gastroenterologists tobe a “difficult” condition with major psychological and psychiatriccomponents. Associations have been shown between irritable bowelsyndrome (IBS) and gastro-oesophageal reflux, between gastro-oesophagealreflux and asthma, and more recently between IBS and bronchialhyper-responsiveness (BHR). These associations are difficult to explainbecause two physiological systems are involved. One possible explanationis that the gastrointestinal and respiratory symptoms in underlyingdisorder, capable of producing symptoms in more than one physiologicalsystem and resulting in an indirect association between seeminglydisparate conditions. A number of candidate mechanisms exist for this:one is a generalized disorder of bronchial, gastrointestinal, and othersmooth muscle.

Irritable bowel syndrome (IBS, or spastic colon) is a symptom-baseddiagnosis characterized by chronic abdominal pain, discomfort, bloating,and alteration of bowel habits. As a functional bowel disorder, IBS hasno known organic cause. Diarrhea or constipation may predominate, orthey may alternate. Historically a diagnosis of exclusion, a diagnosisof IBS can now be made on the basis of symptoms alone, in the absence ofalarm features such as age of onset greater than 50 years, weight loss,gross hematochezia, systemic signs of infection or colitis, or familyhistory of inflammatory bowel disease. Onset of IBS is more likely tooccur after an infection (post-infectious) a stressful life event oronset of maturity.

Several conditions may present themselves as IBS, including coeliacdisease, fructose malabsorption, mild infections, parasitic infectionslike giardiasis, several inflammatory bowel diseases, bile acidmalabsorption, functional chronic constipation, small intestinalbacterial overgrowth, and chronic functional abdominal pain. In IBS,routine clinical tests yield no abnormalities, although the bowels maybe more sensitive to certain stimuli, such as balloon insufflationtesting. The exact cause of IBS is unknown. The most common theory isthat IBS is a disorder of the interaction between the brain and thegastrointestinal tract, although there may also be abnormalities in thegut flora or the immune system.

There is currently a need in the art for new compositions to treatmentor delay of the onset of irritable bowel syndrome (IBS) and itsassociated complications progression.

SUMMARY OF INVENTION

The present invention provides compounds, compositions containing thesecompounds and methods for using the same to treat, prevent and/orameliorate the effects of the conditions such as irritable bowelsyndrome (IBS).

The invention herein provides compositions comprising of formula I orpharmaceutical acceptable salts thereof. The invention also providespharmaceutical compositions comprising one or more compounds of formulaI or intermediates thereof and one or more of pharmaceuticallyacceptable carriers, vehicles or diluents. These compositions may beused in the treatment of irritable bowel syndrome (IBS) and itsassociated complications.

In certain embodiments, the present invention relates to the compoundsand compositions of formula I, or pharmaceutically acceptable saltsthereof,

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

Wherein,

R¹, R³, R⁵ each independently represents H, D, CH₃CO—, CH₃, CD₃CO—,NULL,

R², R⁴, R⁶ each independently represents

n is independently 1, 2, 3, 4 or 5;a is independently 2, 3 or 7;each b is independently 3, 5 or 6;e is independently 1, 2 or 6;c and d are each independently H, D, —OH, —OD, C₁-C₆-alkyl, —NH₂ or—COCH₃.

In certain embodiments, compounds of formula II are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

Wherein,

R¹, R³ each independently represents H, D, CH₃CO—, CH₃, CD₃CO—, NULL,

R², R⁴ each independently represents D, OD,

n is independently 1, 2, 3, 4 or 5;a is independently 2, 3 or 7;each b is independently 3, 5 or 6;e is independently 1, 2 or 6;c and d are each independently H, D, —OH, —OD, C₁-C₆-alkyl, —NH₂ or—COCH₃;within the proviso that there is

Each i independently represents

In certain embodiments, compounds of formula III are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

Wherein,

R¹, R³ each independently represents H, D, CH₃CO—, CH₃, CD₃CO—, NULL,

R², R⁴ each independently represents D, OD,

n is independently 1, 2, 3, 4 or 5;a is independently 2, 3 or 7;each b is independently 3, 5 or 6;e is independently 1, 2 or 6;c and d are each independently H, D, —OH, —OD, C₁-C₆-alkyl, —NH₂ or—COCH₃;within the proviso that there is

Each i independently represents

In certain embodiments, compounds of formula IV are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

Wherein,

R¹, R³, R⁵ each independently represents H, D, CH₃CO—, CH₃, CD₃CO—,NULL,

R², R⁴ each independently represents D, OD,

n is independently 1, 2, 3, 4 or 5;a is independently 2, 3 or 7;each b is independently 3, 5 or 6;e is independently 1, 2 or 6;c and d are each independently H, D, —OH, —OD, C₁-C₆-alkyl, —NH₂ or—COCH₃;within the proviso that there is

Each i independently represents

R⁶ independently represents D, OD, OH or H.

In certain embodiments, compounds of formula V are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

Wherein,

R¹ independently represents H, D, CH₃CO—, CH₃, CD₃CO—, NULL,

R² independently represents D, OD,

n is independently 1, 2, 3, 4 or 5;a is independently 2, 3 or 7;each b is independently 3, 5 or 6;e is independently 1, 2 or 6;c and d are each independently H, D, —OH, —OD, C₁-C₆-alkyl, —NH₂ or—COCH₃;within the proviso that there is

Each i independently represents

In certain embodiments, compounds of formula VI are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

Wherein,

R¹ independently represents H, D, CH₃CO—, CH₃, CD₃CO—, NULL,

R² independently represents D, OD,

n is independently 1, 2, 3, 4 or 5;a is independently 2, 3 or 7;each b is independently 3, 5 or 6;e is independently 1, 2 or 6;c and d are each independently H, D, —OH, —OD, C₁-C₆-alkyl, —NH₂ or—COCH₃;within the proviso that there is

Each i independently represents

In certain embodiments, the present invention relates to the compoundsand compositions of formula VII, or pharmaceutically acceptable solvate,hydrate or polymorphs thereof,

with at least one compound represented by RH, or a mixture thereof

Wherein,

R¹, R³ each independently represents H, D, CH₃CO—, CH₃, CD₃CO—, NULL,

R², R⁴ each independently represents D, OD,

n is independently 1, 2, 3, 4 or 5;a is independently 2, 3 or 7;each b is independently 3, 5 or 6;e is independently 1, 2 or 6;c and d are each independently H, D, —OH, —OD, C₁-C₆-alkyl, —NH₂ or—COCH₃;within the proviso that there is

Each i independently represents

RH independently represents

The compositions of formula VII are typically compounds in the forms ofsalts of mesalamine conjugate and a compound represented (RH) in whichthe mesalamine derivative moiety is protonated and the acid moietyrepresented by RH is at least in partially ionic form. In someinstances, however, for example depending on the pH of the environment,the composition may be in the form of a mixture of mesalamine conjugateand acid components. The invention also provides pharmaceuticalcompositions comprising compositions of formula VII and pharmaceuticallyacceptable excipients.

In certain embodiments, the present invention relates to the compoundsand compositions of formula VIII, or pharmaceutically acceptablesolvate, hydrate or polymorphs thereof,

with at least one compound represented by RH, or a mixture thereof

Wherein,

R¹, R³ each independently represents H, D, CH₃CO—, CH₃, CD₃CO—, NULL,

R², R⁴ each independently represents D, OD,

n is independently 1, 2, 3, 4 or 5;a is independently 2, 3 or 7;each b is independently 3, 5 or 6;e is independently 1, 2 or 6;c and d are each independently H, D, —OH, —OD, C₁-C₆-alkyl, —NH₂ or—COCH₃;within the proviso that there is

Each i independently represents

RH independently represents

The compositions of formula VIII are typically compounds in the forms ofsalts of balsalazide conjugate and a compound represented (RH) in whichthe balsalazide derivative moiety is protonated and the acid moietyrepresented by RH is at least in partially ionic form. In someinstances, however, for example depending on the pH of the environment,the composition may be in the form of a mixture of balsalazide conjugateand acid components. The invention also provides pharmaceuticalcompositions comprising compositions of formula VIII andpharmaceutically acceptable excipients.

In certain embodiments, the present invention relates to the compoundsand compositions of formula IX, or pharmaceutically acceptable solvate,hydrate or polymorphs thereof,

with at least one compound represented by RH, or a mixture thereof

Wherein,

R¹ independently represents H, D, CH₃CO—, CH₃, CD₃CO—, NULL,

R² independently represents D, OD,

n is independently 1, 2, 3, 4 or 5;a is independently 2, 3 or 7;each b is independently 3, 5 or 6;e is independently 1, 2 or 6;c and d are each independently H, D, —OH, —OD, C₁-C₆-alkyl, —NH₂ or—COCH₃;within the proviso that there is

Each i independently represents

RH independently represents

The compositions of formula IX are typically compounds in the forms ofsalts of 2-(dimethylamino)-2-phenylbutan-1-ol conjugate and a compoundrepresented (RH) in which the 2-(dimethylamino)-2-phenylbutan-1-olderivative moiety is protonated and the acid moiety represented by RH isat least in partially ionic form. In some instances, however, forexample depending on the pH of the environment, the composition may bein the form of a mixture of 2-(dimethylamino)-2-phenylbutan-1-olconjugate and acid components. The invention also providespharmaceutical compositions comprising compositions of formula IX andpharmaceutically acceptable excipients.

In certain embodiments, the present invention relates to the compoundsand compositions of formula X, or pharmaceutically acceptable solvate,hydrate or polymorphs thereof,

with at least one compound represented by RH, or a mixture thereof

Wherein,

R¹, R³, R⁵ independently represents H, D, CH₃CO—, CH₃, CD₃CO—, NULL,

R², R⁴ each independently represents D, OD,

n is independently 1, 2, 3, 4 or 5;a is independently 2, 3 or 7;each b is independently 3, 5 or 6;e is independently 1, 2 or 6;c and d are each independently H, D, —OH, —OD, C₁-C₆-alkyl, —NH₂ or—COCH₃;within the proviso that there is

Each i independently represents

RH independently represents

R⁶ independently represents D, OD, OH, H, CD₃ or COCH₃.

The compositions of formula X are typically compounds in the forms ofsalts of mebeverine conjugate and a compound represented (RH) in whichthe mebeverine derivative moiety is protonated and the acid moietyrepresented by RH is at least in partially ionic form. In someinstances, however, for example depending on the pH of the environment,the composition may be in the form of a mixture of mebeverine conjugateand acid components. The invention also provides pharmaceuticalcompositions comprising compositions of formula X and pharmaceuticallyacceptable excipients.

In certain embodiments, the present invention relates to the compoundsand compositions of formula XI, or pharmaceutically acceptable solvate,hydrate or polymorphs thereof,

with at least one compound represented by RH, or a mixture thereof

Wherein,

RH independently represents

The compositions of formula XI are typically compounds in the forms ofsalts of nortrimebutine conjugate and a compound represented (RH) inwhich the nortrimebutine derivative moiety is protonated and the acidmoiety represented by RH is at least in partially ionic form. In someinstances, however, for example depending on the pH of the environment,the composition may be in the form of a mixture of nortrimebutineconjugate and acid components. The invention also providespharmaceutical compositions comprising compositions of formula XI andpharmaceutically acceptable excipients.

In certain embodiments, the present invention relates to the compoundsand compositions of formula XII, or pharmaceutically acceptable solvate,hydrate or polymorphs thereof,

with at least one compound represented by RH, or a mixture thereof

Wherein,

R¹ independently represents H, D, CH₃CO—, CH₃, CD₃CO—, NULL,

R² independently represents D, OD,

n is independently 1, 2, 3, 4 or 5;a is independently 2, 3 or 7;each b is independently 3, 5 or 6;e is independently 1, 2 or 6;c and d are each independently H, D, —OH, —OD, C₁-C₆-alkyl, —NH₂ or—COCH₃;within the proviso that there is

Each i independently represents

RH independently represents

The compositions of formula XII are typically compounds in the forms ofsalts of sulfasalazine conjugate and a compound represented (RH) inwhich the sulfasalazine derivative moiety is in partially ionized formand the base moiety represented by RH is at least in protonated form. Insome instances, however, for example depending on the pH of theenvironment, the composition may be in the form of a mixture ofsulfasalazine conjugate and base components. The invention also providespharmaceutical compositions comprising compositions of formula XII andpharmaceutically acceptable excipients.

In certain embodiments, the present invention relates to the compoundsand compositions of formula XIII, or pharmaceutically acceptablesolvate, hydrate or polymorphs thereof,

with at least one compound represented by RH, or a mixture thereof

Wherein,

R¹, R³ independently represents H, D, CH₃CO—, CH₃, CD₃CO—, NULL,

R², R⁴ each independently represents D, OD,

n is independently 1, 2, 3, 4 or 5;a is independently 2, 3 or 7;each b is independently 3, 5 or 6;e is independently 1, 2 or 6;c and d are each independently H, D, —OH, —OD, C₁-C₆-alkyl, —NH₂ or—COCH₃;within the proviso that there is

Each i independently represents

RH independently represents

The compositions of formula XIII are typically compounds in the forms ofsalts of olsalazine conjugate and a compound represented (RH) in whichthe olsalazine derivative moiety is in partially ionized form and thebase moiety represented by RH is at least in protonated form. In someinstances, however, for example depending on the pH of the environment,the composition may be in the form of a mixture of olsalazine conjugateand base components (RH). The invention also provides pharmaceuticalcompositions comprising compositions of formula XIII andpharmaceutically acceptable excipients.

In certain embodiments, the present invention relates to the compoundsand compositions of formula XIV, or pharmaceutically acceptable solvate,hydrate or polymorphs thereof,

with at least one compound represented by RH, or a mixture thereof

Wherein,

R¹, R³ independently represents H, D, CH₃CO—, CH₃, CD₃CO—, NULL,

R², R⁴ each independently represents D, OD,

n is independently 1, 2, 3, 4 or 5;a is independently 2, 3 or 7;each b is independently 3, 5 or 6;e is independently 1, 2 or 6;c and d are each independently H, D, —OH, —OD, C₁-C₆-alkyl, —NH₂ or—COCH₃;within the proviso that there is

Each i independently represents

RH independently represents

The compositions of formula XIV are typically compounds in the forms ofsalts of balsalazide conjugate and a compound represented (RH) in whichthe balsalazide derivative moiety is in partially ionized form and thebase moiety represented by RH is at least in protonated form. In someinstances, however, for example depending on the pH of the environment,the composition may be in the form of a mixture of balsalazide conjugateand base components (RH). The invention also provides pharmaceuticalcompositions comprising compositions of formula XIV and pharmaceuticallyacceptable excipients.

In certain embodiments, compounds of formula XV are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

Wherein,

R¹, R³ independently represents H, D, CH₃CO—, CH₃, CD₃CO—, NULL,

R², R⁴ each independently represents D, OD,

n is independently 1, 2, 3, 4 or 5;a is independently 2, 3 or 7;each b is independently 3, 5 or 6;e is independently 1, 2 or 6;c and d are each independently H, D, —OH, —OD, C₁-C₆-alkyl, —NH₂ or—COCH₃;within the proviso that there is

Each i independently represents

Herein the application also provides a kit comprising any of thepharmaceutical compositions disclosed herein. The kit may compriseinstructions for use in the treatment of irritable bowel syndrome (IBS)or its related complications.

The application also discloses a pharmaceutical composition comprising apharmaceutically acceptable carrier and any of the compositions herein.In some aspects, the pharmaceutical composition is formulated forsystemic administration, oral administration, sustained release,parenteral administration, injection, subdermal administration, ortransdermal administration.

Herein, the application additionally provides kits comprising thepharmaceutical compositions described herein. The kits may furthercomprise instructions for use in the treatment of irritable bowelsyndrome (IBS) or its related complications.

The compositions described herein have several uses. The presentapplication provides, for example, methods of treating a patientsuffering from inflammatory bowel disease, gastrointestinal diseases,irritable bowel syndrome (IBS) or its related complications manifestedfrom metabolic or genetic conditions or disorders, irritable bowelsyndrome (IBS), chronic diseases or disorders; neurodegenerativedisorders, Hepatology, Cancer, Respiratory, Hematological, Orthopedic,Cardiovascular, Renal, Skin, Vascular or Ocular complications.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used herein, the following terms and phrases shall have the meaningsset forth below. Unless defined otherwise, all technical and scientificterms used herein have the same meaning as commonly understood to one ofordinary skill in the art.

The compounds of the present invention can be present in the form ofpharmaceutically acceptable salts. The compounds of the presentinvention can also be present in the form of pharmaceutically acceptableesters (i.e., the methyl and ethyl esters of the acids of formula I,formula II, formula III, formula IV, formula V, formula VI, formula VII,formula VIII, formula IX, formula X, formula XI, formula XII, formulaXIII, formula XIV or formula XV to be used as prodrugs). The compoundsof the present invention can also be solvated, i.e. hydrated. Thesolvation can be affected in the course of the manufacturing process orcan take place i.e. as a consequence of hygroscopic properties of aninitially anhydrous compound of formula I, formula II, formula III,formula IV, formula V, formula VI, formula VII, formula VIII, formulaIX, formula X, formula XI, formula XII, formula XIII, formula XIV orformula XV (hydration).

Compounds that have the same molecular formula but differ in the natureor sequence of bonding of their atoms or the arrangement of their atomsin space are termed “isomers.” Isomers that differ in the arrangement oftheir atoms in space are termed “stereoisomers.” Diastereomers arestereoisomers with opposite configuration at one or more chiral centerswhich are not enantiomers. Stereoisomers bearing one or more asymmetriccenters that are non-superimposable mirror images of each other aretermed “enantiomers.” When a compound has an asymmetric center, forexample, if a carbon atom is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center or centers and isdescribed by the R- and S-sequencing rules of Cahn, lngold and Prelog,or by the manner in which the molecule rotates the plane of polarizedlight and designated as dextrorotatory or levorotatory (i.e., as (+) or(−)-isomers respectively). A chiral compound can exist as eitherindividual enantiomer or as a mixture thereof. A mixture containingequal proportions of the enantiomers is called a “racemic mixture”.

As used herein, the term “metabolic condition” refers to an Inbornerrors of metabolism (or genetic metabolic conditions) are geneticdisorders that result from a defect in one or more metabolic pathways;specifically, the function of an enzyme is affected and is eitherdeficient or completely absent.

The term “polymorph” as used herein is art-recognized and refers to onecrystal structure of a given compound.

The phrases “parenteral administration” and “administered parenterally”as used herein refer to modes of administration other than enteral andtopical administration, such as injections, and include withoutlimitation intravenous, intramuscular, intrapleural, intravascular,intrapericardial, intraarterial, intrathecal, intracapsular,intraorbital, intracardiac, intradennal, intraperitoneal, transtracheal,subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid,intraspinal and intrastemal injection and infusion.

A “patient,” “subject,” or “host” to be treated by the subject methodmay mean either a human or non-human animal, such as primates, mammals,and vertebrates.

The phrase “pharmaceutically acceptable” is art-recognized. In certainembodiments, the term includes compositions, polymers and othermaterials and/or dosage forms which are, within the scope of soundmedical judgment, suitable for use in contact with the tissues ofmammals, human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The phrase “pharmaceutically acceptable carrier” is art-recognized, andincludes, for example, pharmaceutically acceptable materials,compositions or vehicles, such as a liquid or solid filler, diluent,solvent or encapsulating material involved in carrying or transportingany subject composition, from one organ, or portion of the body, toanother organ, or portion of the body. Each carrier must be “acceptable”in the sense of being compatible with the other ingredients of a subjectcomposition and not injurious to the patient. In certain embodiments, apharmaceutically acceptable carrier is non-pyrogenic. Some examples ofmaterials which may serve as pharmaceutically acceptable carriersinclude: (1) sugars, such as lactose, glucose and sucrose; (2) starches,such as corn starch and potato starch; (3) cellulose, and itsderivatives, such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7)talc; (8) cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21)other non-toxic compatible substances employed in pharmaceuticalformulations.

The term “prodrug” is intended to encompass compounds that, underphysiological conditions, are converted into the therapeutically activeagents of the present invention. A common method for making a prodrug isto include selected moieties that are hydrolyzed under physiologicalconditions to reveal the desired molecule. In other embodiments, theprodrug is converted by an enzymatic activity of the host animal.

The term “prophylactic or therapeutic” treatment is art-recognized andincludes administration to the host of one or more of the subjectcompositions. If it is administered prior to clinical manifestation ofthe unwanted condition (e.g., disease or other unwanted state of thehost animal) then the treatment is prophylactic, i.e., it protects thehost against developing the unwanted condition, whereas if it isadministered after manifestation of the unwanted condition, thetreatment is therapeutic, (i.e., it is intended to diminish, ameliorate,or stabilize the existing unwanted condition or side effects thereof).

The term “predicting” as used herein refers to assessing the probabilityrelated diseases patient will suffer from abnormalities or complicationand/or terminal bowel disease or failure and/or death (i.e. mortality)within a defined time window (predictive window) in the future. Themortality may be caused by the central nervous system or complication.The predictive window is an interval in which the subject will developone or more of the said complications according to the predictedprobability. The predictive window may be the entire remaining lifespanof the subject upon analysis by the method of the present invention.

The term “treating” is art-recognized and includes preventing a disease,disorder or condition from occurring in an animal which may bepredisposed to the disease, disorder and/or condition but has not yetbeen diagnosed as having it; inhibiting the disease, disorder orcondition, e.g., impeding its progress; and relieving the disease,disorder, or condition, e.g., causing regression of the disease,disorder and/or condition. Treating the disease or condition includesameliorating at least one symptom of the particular disease orcondition, even if the underlying pathophysiology is not affected, suchas treating the metabolic syndrome and diabetes related disordersincludes such as Inflammatory bowel disease, Irritable bowel syndrome(IBS) includes such as coeliac disease, fructose malabsorption, mildinfections, parasitic infections like giardiasis, several inflammatorybowel diseases, bile acid malabsorption, functional chronicconstipation, small intestinal bacterial overgrowth, and chronicfunctional abdominal pain and other related diseases or any othermedical condition, is well understood in the art, and includesadministration of a composition which reduces the frequency of, ordelays the onset of, symptoms of a medical condition in a subjectrelative to a subject which does not receive the composition. of asubject by administration of an agent even though such agent does nottreat the cause of the condition. The term “treating”, “treat” or“treatment” as used herein includes curative, preventative (e.g.,prophylactic), adjunct and palliative treatment.

The phrase “therapeutically effective amount” is an art-recognized term.In certain embodiments, the term refers to an amount of a salt orcomposition disclosed herein that produces some desired effect at areasonable benefit/risk ratio applicable to any medical treatment. Incertain embodiments, the term refers to that amount necessary orsufficient to eliminate or reduce medical symptoms for a period of time.The effective amount may vary depending on such factors as the diseaseor condition being treated, the particular targeted constructs beingadministered, the size of the subject, or the severity of the disease orcondition. One of ordinary skill in the art may empirically determinethe effective amount of a particular composition without necessitatingundue experimentation.

In certain embodiments, the pharmaceutical compositions described hereinare formulated in a manner such that said compositions will be deliveredto a patient in a therapeutically effective amount, as part of aprophylactic or therapeutic treatment. The desired amount of thecomposition to be administered to a patient will depend on absorption,inactivation, and excretion rates of the drug as well as the deliveryrate of the salts and compositions from the subject compositions. It isto be noted that dosage values may also vary with the severity of thecondition to be alleviated. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of thecompositions. Typically, dosing will be determined using techniquesknown to one skilled in the art.

Additionally, the optimal concentration and/or quantities or amounts ofany particular salt or composition may be adjusted to accommodatevariations in the treatment parameters. Such treatment parametersinclude the clinical use to which the preparation is put, e.g., the sitetreated, the type of patient, e.g., human or non-human, adult or child,and the nature of the disease or condition.

In certain embodiments, the dosage of the subject compositions providedherein may be determined by reference to the plasma concentrations ofthe therapeutic composition or other encapsulated materials. Forexample, the maximum plasma concentration (Cmax) and the area under theplasma concentration-time curve from time 0 to infinity may be used.

When used with respect to a pharmaceutical composition or othermaterial, the term “sustained release” is art-recognized. For example, asubject composition which releases a substance over time may exhibitsustained release characteristics, in contrast to a bolus typeadministration in which the entire amount of the substance is madebiologically available at one time. For example, in particularembodiments, upon contact with body fluids including blood, spinalfluid, mucus secretions, lymph or the like, one or more of thepharmaceutically acceptable excipients may undergo gradual or delayeddegradation (e.g., through hydrolysis) with concomitant release of anymaterial incorporated therein, e.g., an therapeutic and/or biologicallyactive salt and/or composition, for a sustained or extended period (ascompared to the release from a bolus). This release may result inprolonged delivery of therapeutically effective amounts of any of thetherapeutic agents disclosed herein.

The phrases “systemic administration,” “administered systemically,”“peripheral administration” and “administered peripherally” areart-recognized, and include the administration of a subject composition,therapeutic or other material at a site remote from the disease beingtreated. Administration of an agent for the disease being treated, evenif the agent is subsequently distributed systemically, may be termed“local” or “topical” or “regional” administration, other than directlyinto the central nervous system, e.g., by subcutaneous administration,such that it enters the patient's system and, thus, is subject tometabolism and other like processes.

The phrase “therapeutically effective amount” is an art-recognized term.In certain embodiments, the term refers to an amount of a salt orcomposition disclosed herein that produces some desired effect at areasonable benefit/risk ratio applicable to any medical treatment. Incertain embodiments, the term refers to that amount necessary orsufficient to eliminate or reduce medical symptoms for a period of time.The effective amount may vary depending on such factors as the diseaseor condition being treated, the particular targeted constructs beingadministered, the size of the subject, or the severity of the disease orcondition. One of ordinary skill in the art may empirically determinethe effective amount of a particular composition without necessitatingundue experimentation.

The present disclosure also contemplates prodrugs of the compositionsdisclosed herein, as well as pharmaceutically acceptable salts of saidprodrugs.

This application also discloses a pharmaceutical composition comprisinga pharmaceutically acceptable carrier and the composition of a compoundof Formula I, formula II, formula III, formula IV, formula V, formulaVI, formula VII, formula VIII, formula IX, formula X, formula XI,formula XII, formula XIII, formula XIV or formula XV may be formulatedfor systemic or topical or oral administration. The pharmaceuticalcomposition may be also formulated for oral administration, oralsolution, injection, subdermal administration, or transdermaladministration. The pharmaceutical composition may further comprise atleast one of a pharmaceutically acceptable stabilizer, diluent,surfactant, filler, binder, and lubricant.

In many embodiments, the pharmaceutical compositions described hereinwill incorporate the disclosed compounds and compositions (Formula I andFormula II) to be delivered in an amount sufficient to deliver to apatient a therapeutically effective amount of a compound of formula I,formula II, formula III, formula IV, formula V, formula VI, formula VII,formula VIII, formula IX, formula X, formula XI, formula XII, formulaXIII, formula XIV or formula XV or composition as part of a prophylacticor therapeutic treatment. The desired concentration of formula I,formula II, formula III, formula IV, formula V, formula VI, formula VII,formula VIII, formula IX, formula X, formula XI, formula XII, formulaXIII, formula XIV or formula XV or its pharmaceutical acceptable saltswill depend on absorption, inactivation, and excretion rates of the drugas well as the delivery rate of the salts and compositions from thesubject compositions. It is to be noted that dosage values may also varywith the severity of the condition to be alleviated. It is to be furtherunderstood that for any particular subject, specific dosage regimensshould be adjusted over time according to the individual need and theprofessional judgment of the person administering or supervising theadministration of the compositions. Typically, dosing will be determinedusing techniques known to one skilled in the art.

Additionally, the optimal concentration and/or quantities or amounts ofany particular compound of formula I, formula II, formula III, formulaIV, formula V, formula VI, formula VII, formula VIII, formula IX,formula X, formula XI, formula XII, formula XIII, formula XIV or formulaXV may be adjusted to accommodate variations in the treatmentparameters. Such treatment parameters include the clinical use to whichthe preparation is put, e.g., the site treated, the type of patient,e.g., human or non-human, adult or child, and the nature of the diseaseor condition.

The concentration and/or amount of any compound of formula I, formulaII, formula III, formula IV, formula V, formula VI, formula VII, formulaVIII, formula IX, formula X, formula XI, formula XII, formula XIII,formula XIV or formula XV may be readily identified by routine screeningin animals, e.g., rats, by screening a range of concentration and/oramounts of the material in question using appropriate assays. Knownmethods are also available to assay local tissue concentrations,diffusion rates of the salts or compositions, and local blood flowbefore and after administration of therapeutic formulations disclosedherein. One such method is microdialysis, as reviewed by T. E. Robinsonet al., 1991, microdialysis in the neurosciences, Techniques, volume 7,Chapter 1. The methods reviewed by Robinson may be applied, in brief, asfollows. A microdialysis loop is placed in situ in a test animal.Dialysis fluid is pumped through the loop. When compounds with formulaI, formula II, formula III, formula IV, formula V, formula VI, formulaVII, formula VIII, formula IX, formula X, formula XI, formula XII,formula XIII, formula XIV or formula XV such as those disclosed hereinare injected adjacent to the loop, released drugs are collected in thedialysate in proportion to their local tissue concentrations. Theprogress of diffusion of the salts or compositions may be determinedthereby with suitable calibration procedures using known concentrationsof salts or compositions.

In certain embodiments, the dosage of the subject compounds of formulaI, formula II, formula III, formula IV, formula V, formula VI, formulaVII, formula VIII, formula IX, formula X, formula XI, formula XII,formula XIII, formula XIV or formula XV provided herein may bedetermined by reference to the plasma concentrations of the therapeuticcomposition or other encapsulated materials. For example, the maximumplasma concentration (Cmax) and the area under the plasmaconcentration-time curve from time 0 to infinity may be used.

Generally, in carrying out the methods detailed in this application, aneffective dosage for the compounds of Formulas I, Formula II, formulaIII, formula IV, formula V, formula VI, formula VII, formula VIII,formula IX, formula X is in the range of about 0.01 mg/kg/day to about100 mg/kg/day in single or divided doses, for instance 0.01 mg/kg/day toabout 50 mg/kg/day in single or divided doses. The compounds of FormulasI may be administered at a dose of, for example, less than 0.2mg/kg/day, 0.5 mg/kg/day, 1.0 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, 20mg/kg/day, 30 mg/kg/day, or 40 mg/kg/day. Compounds of Formula I,formula II, formula III, formula IV, formula V, formula VI, formula VII,formula VIII, formula IX, formula X, formula XI, formula XII, formulaXIII, formula XIV or formula XV may also be administered to a humanpatient at a dose of, for example, between 0.1 mg and 1000 mg, between 5mg and 80 mg, or less than 1.0, 9.0, 12.0, 20.0, 50.0, 75.0, 100, 300,400, 500, 800, 1000, 2000, 5000 mg per day. In certain embodiments, thecompositions herein are administered at an amount that is less than 95%,90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% of the compound offormula I, formula II, formula III, formula IV, formula V, formula VI,formula VII, formula VIII, formula IX, formula X, formula XI, formulaXII, formula XIII, formula XIV or formula XV required for the sametherapeutic benefit.

An effective amount of the compounds of formula I, formula II, formulaIII, formula IV, formula V, formula VI, formula VII, formula VIII,formula IX, formula X, formula XI, formula XII, formula XIII, formulaXIV or formula XV described herein refers to the amount of one of saidsalts or compositions which is capable of inhibiting or preventing adisease.

An effective amount may be sufficient to prohibit, treat, alleviate,ameliorate, halt, restrain, slow or reverse the progression, or reducethe severity of a complication resulting from nerve damage ordemyelization and/or elevated reactive oxidative-nitrosative speciesand/or abnormalities in neurotransmitter homeostasis's, in patients whoare at risk for such complications. As such, these methods include bothmedical therapeutic (acute) and/or prophylactic (prevention)administration as appropriate. The amount and timing of compositionsadministered will, of course, be dependent on the subject being treated,on the severity of the affliction, on the manner of administration andon the judgment of the prescribing physician. Thus, because ofpatient-to-patient variability, the dosages given above are a guidelineand the physician may titrate doses of the drug to achieve the treatmentthat the physician considers appropriate for the patient. In consideringthe degree of treatment desired, the physician must balance a variety offactors such as age of the patient, presence of preexisting disease, aswell as presence of other diseases.

The compositions provided by this application may be administered to asubject in need of treatment by a variety of conventional routes ofadministration, including orally, topically, parenterally, e.g.,intravenously, subcutaneously or intramedullary. Further, thecompositions may be administered intranasally, as a rectal suppository,or using a “flash” formulation, i.e., allowing the medication todissolve in the mouth without the need to use water. Furthermore, thecompositions may be administered to a subject in need of treatment bycontrolled release dosage forms, site specific drug delivery,transdermal drug delivery, patch (active/passive) mediated drugdelivery, by stereotactic injection, or in nanoparticles.

The compositions may be administered alone or in combination withpharmaceutically acceptable carriers, vehicles or diluents, in eithersingle or multiple doses. Suitable pharmaceutical carriers, vehicles anddiluents include inert solid diluents or fillers, sterile aqueoussolutions and various organic solvents. The pharmaceutical compositionsformed by combining the compositions and the pharmaceutically acceptablecarriers, vehicles or diluents are then readily administered in avariety of dosage forms such as tablets, powders, lozenges, syrups,injectable solutions and the like. These pharmaceutical compositionscan, if desired, contain additional ingredients such as flavorings,binders, excipients and the like. Thus, for purposes of oraladministration, tablets containing various excipients such asL-arginine, sodium citrate, calcium carbonate and calcium phosphate maybe employed along with various disintegrates such as starch, alginicacid and certain complex silicates, together with binding agents such aspolyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often useful for tabletting purposes. Solid compositions of asimilar type may also be employed as fillers in soft and hard filledgelatin capsules. Appropriate materials for this include lactose or milksugar and high molecular weight polyethylene glycols. When aqueoussuspensions or elixirs are desired for oral administration, theessential active ingredient therein may be combined with varioussweetening or flavoring agents, coloring matter or dyes and, if desired,emulsifying or suspending agents, together with diluents such as water,ethanol, propylene glycol, glycerin and combinations thereof. Thecompounds of formula I, formula II, formula III, formula IV, formula V,formula VI, formula VII, formula VIII, formula IX, formula X, formulaXI, formula XII, formula XIII, formula XIV or formula XV may alsocomprise enterically coated comprising of various excipients, as is wellknown in the pharmaceutical art.

For parenteral administration, solutions of the compositions may beprepared in (for example) sesame or peanut oil, aqueous propyleneglycol, or in sterile aqueous solutions may be employed. Such aqueoussolutions should be suitably buffered if necessary and the liquiddiluent first rendered isotonic with sufficient saline or glucose. Theseparticular aqueous solutions are especially suitable for intravenous,intramuscular, subcutaneous and intraperitoneal administration. In thisconnection, the sterile aqueous media employed are all readily availableby standard techniques known to those skilled in the art.

The formulations, for instance tablets, may contain e.g. 10 to 100, 50to 250, 150 to 500 mg, or 350 to 800 mg e.g. 10, 50, 100, 300, 500, 700,800 mg of the compounds of formula I, formula II, formula III, formulaIV, formula V, formula VI, formula VII, formula VIII, formula IX,formula X, formula XI, formula XII, formula XIII, formula XIV or formulaXV disclosed herein, for instance, compounds of formula I, formula II,formula III, formula IV, formula V, formula VI, formula VII, formulaVIII, formula IX, formula X, formula XI, formula XII, formula XIII,formula XIV or formula XV or pharmaceutical acceptable salts of acompounds of formula I, formula II, formula III, formula IV, formula V,formula VI, formula VII, formula VIII, formula IX, formula X, formulaXI, formula XII, formula XIII, formula XIV or formula XV.

Generally, a composition as described herein may be administered orally,or parenterally (e.g., intravenous, intramuscular, subcutaneous orintramedullary). Topical administration may also be indicated, forexample, where the patient is suffering from gastrointestinal disorderthat prevent oral administration, or whenever the medication is bestapplied to the surface of a tissue or organ as determined by theattending physician. Localized administration may also be indicated, forexample, when a high dose is desired at the target tissue or organ. Forbuccal administration the active composition may take the form oftablets or lozenges formulated in a conventional manner

The dosage administered will be dependent upon the identity of theneurological disease; the type of host involved, including its age,health and weight; the kind of concurrent treatment, if any; thefrequency of treatment and therapeutic ratio.

Illustratively, dosage levels of the administered active ingredientsare: intravenous, 0.1 to about 200 mg/kg; intramuscular, 1 to about 500mg/kg; orally, 5 to about 1000 mg/kg; intranasal instillation, 5 toabout 1000 mg/kg; and aerosol, 5 to about 1000 mg/kg of host bodyweight.

Expressed in terms of concentration, an active ingredient can be presentin the compositions of the present invention for localized use about thecutis, intranasally, pharyngolaryngeally, bronchially, intravaginally,rectally, or ocularly in a concentration of from about 0.01 to about 50%w/w of the composition; preferably about 1 to about 20% w/w of thecomposition; and for parenteral use in a concentration of from about0.05 to about 50% w/v of the composition and preferably from about 5 toabout 20% w/v.

The compositions of the present invention are preferably presented foradministration to humans and animals in unit dosage forms, such astablets, capsules, pills, powders, granules, suppositories, sterileparenteral solutions or suspensions, sterile non-parenteral solutions ofsuspensions, and oral solutions or suspensions and the like, containingsuitable quantities of an active ingredient. For oral administrationeither solid or fluid unit dosage forms can be prepared.

As discussed above, the tablet core contains one or more hydrophilicpolymers. Suitable hydrophilic polymers include, but are not limited to,water swellable cellulose derivatives, polyalkylene glycols,thermoplastic polyalkylene oxides, acrylic polymers, hydrocolloids,clays, gelling starches, swelling cross-linked polymers, and mixturesthereof. Examples of suitable water swellable cellulose derivativesinclude, but are not limited to, sodium carboxymethylcellulose,cross-linked hydroxypropylcellulose, hydroxypropyl cellulose (HPC),hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose,hydroxybutylcellulose, hydroxyphenylcellulose, hydroxyethylcellulose(HEC), hydroxypentylcellulose, hydroxypropylethylcellulose,hydroxypropylbutylcellulose, and hydroxypropylethylcellulose, andmixtures thereof. Examples of suitable polyalkylene glycols include, butare not limited to, polyethylene glycol. Examples of suitablethermoplastic polyalkylene oxides include, but are not limited to,poly(ethylene oxide). Examples of suitable acrylic polymers include, butare not limited to, potassium methacrylatedivinylbenzene copolymer,polymethylmethacrylate, high-molecular weight crosslinked acrylic acidhomopolymers and copolymers such as those commercially available fromNoveon Chemicals under the tradename CARBOPOL™. Examples of suitablehydrocolloids include, but are not limited to, alginates, agar, guargum, locust bean gum, kappa carrageenan, iota carrageenan, tara, gumarabic, tragacanth, pectin, xanthan gum, gellan gum, maltodextrin,galactomannan, pusstulan, laminarin, scleroglucan, gum arabic, inulin,pectin, gelatin, whelan, rhamsan, zooglan, methylan, chitin,cyclodextrin, chitosan, and mixtures thereof. Examples of suitable claysinclude, but are not limited to, smectites such as bentonite, kaolin,and laponite; magnesium trisilicate; magnesium aluminum silicate; andmixtures thereof. Examples of suitable gelling starches include, but arenot limited to, acid hydrolyzed starches, swelling starches such assodium starch glycolate and derivatives thereof, and mixtures thereof.Examples of suitable swelling cross-linked polymers include, but are notlimited to, cross-linked polyvinyl pyrrolidone, cross-linked agar, andcross-linked carboxymethylcellulose sodium, and mixtures thereof.

The carrier may contain one or more suitable excipients for theformulation of tablets. Examples of suitable excipients include, but arenot limited to, fillers, adsorbents, binders, disintegrants, lubricants,glidants, release-modifying excipients, superdisintegrants,antioxidants, and mixtures thereof.

Suitable binders include, but are not limited to, dry binders such aspolyvinyl pyrrolidone and hydroxypropylmethylcellulose; wet binders suchas water-soluble polymers, including hydrocolloids such as acacia,alginates, agar, guar gum, locust bean, carrageenan,carboxymethylcellulose, tara, gum arabic, tragacanth, pectin, xanthan,gellan, gelatin, maltodextrin, galactomannan, pusstulan, laminarin,scleroglucan, inulin, whelan, rhamsan, zooglan, methylan, chitin,cyclodextrin, chitosan, polyvinyl pyrrolidone, cellulosics, sucrose, andstarches; and mixtures thereof. Suitable disintegrants include, but arenot limited to, sodium starch glycolate, cross-linkedpolyvinylpyrrolidone, cross-linked carboxymethylcellulose, starches,microcrystalline cellulose, and mixtures thereof.

Suitable lubricants include, but are not limited to, long chain fattyacids and their salts, such as magnesium stearate and stearic acid,talc, glycerides waxes, and mixtures thereof. Suitable glidants include,but are not limited to, colloidal silicon dioxide. Suitablerelease-modifying excipients include, but are not limited to, insolubleedible materials, pH-dependent polymers, and mixtures thereof.

Suitable insoluble edible materials for use as release-modifyingexcipients include, but are not limited to, water-insoluble polymers andlow-melting hydrophobic materials, copolymers thereof, and mixturesthereof. Examples of suitable water-insoluble polymers include, but arenot limited to, ethylcellulose, polyvinyl alcohols, polyvinyl acetate,polycaprolactones, cellulose acetate and its derivatives, acrylates,methacrylates, acrylic acid copolymers, copolymers thereof, and mixturesthereof. Suitable low-melting hydrophobic materials include, but are notlimited to, fats, fatty acid esters, phospholipids, waxes, and mixturesthereof. Examples of suitable fats include, but are not limited to,hydrogenated vegetable oils such as for example cocoa butter,hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenatedsunflower oil, and hydrogenated soybean oil, free fatty acids and theirsalts, and mixtures thereof. Examples of suitable fatty acid estersinclude, but are not limited to, sucrose fatty acid esters, mono-, di-,and triglycerides, glyceryl behenate, glyceryl palmitostearate, glycerylmonostearate, glyceryl tristearate, glyceryl trilaurylate, glycerylmyristate, GlycoWax-932, lauroyl macrogol-32 glycerides, stearoylmacrogol-32 glycerides, and mixtures thereof. Examples of suitablephospholipids include phosphotidyl choline, phosphotidyl serene,phosphotidyl enositol, phosphotidic acid, and mixtures thereof. Examplesof suitable waxes include, but are not limited to, carnauba wax,spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystallinewax, and paraffin wax; fat-containing mixtures such as chocolate, andmixtures thereof. Examples of super disintegrants include, but are notlimited to, croscarmellose sodium, sodium starch glycolate andcross-linked povidone (crospovidone). In one embodiment the tablet corecontains up to about 5 percent by weight of such super disintegrant.

Examples of antioxidants include, but are not limited to, tocopherols,ascorbic acid, sodium pyrosulfite, butylhydroxytoluene, butylatedhydroxyanisole, edetic acid, and edetate salts, and mixtures thereof.Examples of preservatives include, but are not limited to, citric acid,tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid, andsorbic acid, and mixtures thereof.

In one embodiment, the immediate release coating has an averagethickness of at least 50 microns, such as from about 50 microns to about2500 microns; e.g., from about 250 microns to about 1000 microns. Inembodiment, the immediate release coating is typically compressed at adensity of more than about 0.9 g/cc, as measured by the weight andvolume of that specific layer.

In one embodiment, the immediate release coating contains a firstportion and a second portion, wherein at least one of the portionscontains the second pharmaceutically active agent. In one embodiment,the portions contact each other at a center axis of the tablet. In oneembodiment, the first portion includes the first pharmaceutically activeagent and the second portion includes the second pharmaceutically activeagent.

In one embodiment, the first portion contains the first pharmaceuticallyactive agent and the second portion contains the second pharmaceuticallyactive agent. In one embodiment, one of the portions contains a thirdpharmaceutically active agent. In one embodiment one of the portionscontains a second immediate release portion of the same pharmaceuticallyactive agent as that contained in the tablet core.

In one embodiment, the outer coating portion is prepared as a dry blendof materials prior to addition to the coated tablet core. In anotherembodiment the outer coating portion is included of a dried granulationincluding the pharmaceutically active agent.

Formulations with different drug release mechanisms described abovecould be combined in a final dosage form containing single or multipleunits. Examples of multiple units include multilayer tablets, capsulescontaining tablets, beads, or granules in a solid or liquid form.Typical, immediate release formulations include compressed tablets,gels, films, coatings, liquids and particles that can be encapsulated,for example, in a gelatin capsule. Many methods for preparing coatings,covering or incorporating drugs, are known in the art.

The immediate release dosage, unit of the dosage form, i.e., a tablet, aplurality of drug-containing beads, granules or particles, or an outerlayer of a coated core dosage form, contains a therapeutically effectivequantity of the active agent with conventional pharmaceuticalexcipients. The immediate release dosage unit may or may not be coated,and may or may not be admixed with the delayed release dosage unit orunits (as in an encapsulated mixture of immediate releasedrug-containing granules, particles or beads and delayed releasedrug-containing granules or beads).

Extended release formulations are generally prepared as diffusion orosmotic systems, for example, as described in “Remington—The Science andPractice of Pharmacy”, 20th. Ed., Lippincott Williams & Wilkins,Baltimore, Md., 2000). A diffusion system typically consists of one oftwo types of devices, reservoir and matrix, which are wellknown anddescribed in die art. The matrix devices are generally prepared bycompressing the drug with a slowly dissolving polymer carrier into atablet form.

An immediate release portion can be added to the extended release systemby means of either applying an immediate release layer on top of theextended release core; using coating or compression processes or in amultiple unit system such as a capsule containing extended and immediaterelease beads.

Delayed release dosage formulations are created by coating a soliddosage form with a film of a polymer which is insoluble in the acidenvironment of the stomach, but soluble in the neutral environment ofsmall intestines. The delayed release dosage units can be prepared, forexample, by coating a drug or a drug-containing composition with aselected coating material. The drug-containing composition may be atablet for incorporation into a capsule, a tablet for use as an innercore in a “coated core” dosage form, or a plurality of drug-containingbeads, particles or granules, for incorporation into either a tablet orcapsule.

A pulsed release dosage form is one that mimics a multiple dosingprofile without repeated dosing and typically allows at least a twofoldreduction in dosing frequency as compared to the drug presented as aconventional dosage form (e.g., as a solution or prompt drug-releasing,conventional solid dosage form). A pulsed release profile ischaracterized by a time period of no release (lag time) or reducedrelease followed by rapid drug release.

Each dosage form contains a therapeutically effective amount of activeagent. In one embodiment of dosage forms that mimic a twice daily dosingprofile, approximately 30 wt. % to 70 wt. %, preferably 40 wt. % to 60wt. %, of the total amount of active agent in the dosage form isreleased in the initial pulse, and, correspondingly approximately 70 wt.% to 3.0 wt. %, preferably 60 wt. % to 40 wt. %, of the total amount ofactive agent in the dosage form is released in the second pulse. Fordosage forms mimicking the twice daily dosing profile, the second pulseis preferably released approximately 3 hours to less than 14 hours, andmore preferably approximately 5 hours to 12 hours, followingadministration.

Another dosage form contains a compressed tablet or a capsule having adrug-containing immediate release dosage unit, a delayed release dosageunit and an optional second delayed release dosage unit. In this dosageform, the immediate release dosage unit contains a plurality of beads,granules particles that release drug substantially immediately followingoral administration to provide an initial dose. The delayed releasedosage unit contains a plurality of coated beads or granules, whichrelease drug approximately 3 hours to 14 hours following oraladministration to provide a second dose.

For purposes of transdermal (e.g., topical) administration, dilutesterile, aqueous or partially aqueous solutions (usually in about 0.1%to 5% concentration), otherwise similar to the above parenteralsolutions, may be prepared.

Methods of preparing various pharmaceutical compositions with a certainamount of one or more compounds of formula I, formula II, formula III,formula IV, formula V, formula VI, formula VII, formula VIII, formulaIX, formula X, formula XI, formula XII, formula XIII, formula XIV orformula XV or other active agents are known, or will be apparent inlight of this disclosure, to those skilled in this art. For examples ofmethods of preparing pharmaceutical compositions, see Remington'sPharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 19thEdition (1995).

In addition, in certain embodiments, subject compositions of the presentapplication maybe lyophilized or subjected to another appropriate dryingtechnique such as spray drying. The subject compositions may beadministered once, or may be divided into a number of smaller doses tobe administered at varying intervals of time, depending in part on therelease rate of the compositions and the desired dosage.

Formulations useful in the methods provided herein include thosesuitable for oral, nasal, topical (including buccal and sublingual),rectal, vaginal, aerosol and/or parenteral administration. Theformulations may conveniently be presented in unit dosage form and maybe prepared by any methods well known in the art of pharmacy. The amountof a subject composition which may be combined with a carrier materialto produce a single dose may vary depending upon the subject beingtreated, and the particular mode of administration.

Methods of preparing these formulations or compositions include the stepof bringing into association subject compositions with the carrier and,optionally, one or more accessory ingredients. In general, theformulations are prepared by uniformly and intimately bringing intoassociation a subject composition with liquid carriers, or finelydivided solid carriers, or both, and then, if necessary, shaping theproduct.

The compounds of formula I, formula II, formula III, formula IV, formulaV, formula VI, formula VII, formula VIII, formula IX, formula X, formulaXI, formula XII, formula XIII, formula XIV or formula XV describedherein may be administered in inhalant or aerosol formulations. Theinhalant or aerosol formulations may comprise one or more agents, suchas adjuvants, diagnostic agents, imaging agents, or therapeutic agentsuseful in inhalation therapy. The final aerosol formulation may forexample contain 0.005-90% w/w, for instance 0.005-50%, 0.005-5% w/w, or0.01-1.0% w/w, of medicament relative to the total weight of theformulation.

In solid dosage forms for oral administration (capsules, tablets, pills,dragees, powders, granules and the like), the subject composition ismixed with one or more pharmaceutically acceptable carriers and/or anyof the following: (1) fillers or extenders, such as starches, lactose,sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as,for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol;(4) disintegrating agents, such as agar-agar, calcium carbonate, potatoor tapioca starch, alginic acid, certain silicates, and sodiumcarbonate; (5) solution retarding agents, such as paraffin; (6)absorption accelerators, such as quaternary ammonium compounds; (7)wetting agents, such as, for example, acetyl alcohol and glycerolmonostearate; (8) absorbents, such as kaolin and bentonite clay; (9)lubricants, such a talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and(10) coloring agents. In the case of capsules, tablets and pills, thepharmaceutical compositions may also comprise buffering agents. Solidcompositions of a similar type may also be employed as fillers in softand hard-filled gelatin capsules using lactose or milk sugars, as wellas high molecular weight polyethylene glycols and the like.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the subject compositions, the liquid dosageforms may contain inert diluents commonly used in the art, such as, forexample, water or other solvents, solubilizing agents and emulsifiers,such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, oils (in particular, cottonseed, corn, peanut, sunflower,soybean, olive, castor, and sesame oils), glycerol, tetrahydrofurylalcohol, polyethylene glycols and fatty acid esters of sorbitan, andmixtures thereof.

Suspensions, in addition to the subject compositions, may containsuspending agents such as, for example, ethoxylated isostearyl alcohols,polyoxyethylene sorbitol, and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth,and mixtures thereof.

Formulations for rectal or vaginal administration may be presented as asuppository, which may be prepared by mixing a subject composition withone or more suitable non-irritating carriers comprising, for example,cocoa butter, polyethylene glycol, a suppository wax, or a salicylate,and which is solid at room temperature, but liquid at body temperatureand, therefore, will melt in the appropriate body cavity and release theencapsulated compound(s) and composition(s). Formulations which aresuitable for vaginal administration also include pessaries, tampons,creams, gels, pastes, foams, or spray formulations containing suchcarriers as are known in the art to be appropriate.

Dosage forms for transdermal administration include powders, sprays,ointments, pastes, creams, lotions, gels, solutions, patches, andinhalants. A subject composition may be mixed under sterile conditionswith a pharmaceutically acceptable carrier, and with any preservatives,buffers, or propellants that may be required. For transdermaladministration, the complexes may include lipophilic and hydrophilicgroups to achieve the desired water solubility and transport properties.

The ointments, pastes, creams and gels may contain, in addition tosubject compositions, other carriers, such as animal and vegetable fats,oils, waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures thereof. Powders and sprays may contain, in additionto a subject composition, excipients such as lactose, talc, silicicacid, aluminum hydroxide, calcium silicates and polyamide powder, ormixtures of such substances. Sprays may additionally contain customarypropellants, such as chlorofluorohydrocarbons and volatile unsubstitutedhydrocarbons, such as butane and propane.

Methods of delivering a composition or compositions via a transdermalpatch are known in the art. Exemplary patches and methods of patchdelivery are described in U.S. Pat. Nos. 6,974,588, 6,564,093,6,312,716, 6,440,454, 6,267,983, 6,239,180, and 6,103,275.

In another embodiment, a transdermal patch may comprise: a substratesheet comprising a composite film formed of a resin compositioncomprising 100 parts by weight of a polyvinyl chloride-polyurethanecomposite and 2-10 parts by weight of astyrene-ethylene-butylene-styrene copolymer, a first adhesive layer onthe one side of the composite film, and a polyalkylene terephthalatefilm adhered to the one side of the composite film by means of the firstadhesive layer, a primer layer which comprises a saturated polyesterresin and is formed on the surface of the polyalkylene terephthalatefilm; and a second adhesive layer comprising a styrene-diene-styreneblock copolymer containing a pharmaceutical agent layered on the primerlayer. A method for the manufacture of the above-mentioned substratesheet comprises preparing the above resin composition molding the resincomposition into a composite film by a calendar process, and thenadhering a polyalkylene terephthalate film on one side of the compositefilm by means of an adhesive layer thereby forming the substrate sheet,and forming a primer layer comprising a saturated polyester resin on theouter surface of the polyalkylene terephthalate film.

Another type of patch comprises incorporating the drug directly in apharmaceutically acceptable adhesive and laminating the drug-containingadhesive onto a suitable backing member, e.g. a polyester backingmembrane. The drug should be present at a concentration which will notaffect the adhesive properties, and at the same time deliver therequired clinical dose.

Transdermal patches may be passive or active. Passive transdermal drugdelivery systems currently available, such as the nicotine, estrogen andnitroglycerine patches, deliver small-molecule drugs. Many of the newlydeveloped proteins and peptide drugs are too large to be deliveredthrough passive transdermal patches and may be delivered usingtechnology such as electrical assist (iontophoresis) for large-moleculedrugs.

Iontophoresis is a technique employed for enhancing the flux of ionizedsubstances through membranes by application of electric current. Oneexample of an iontophoretic membrane is given in U.S. Pat. No. 5,080,646to Theeuwes. The principal mechanisms by which iontophoresis enhancesmolecular transport across the skin are (a) repelling a charged ion froman electrode of the same charge, (b) electroosmosis, the convectivemovement of solvent that occurs through a charged pore in response thepreferential passage of counter-ions when an electric field is appliedor (c) increase skin permeability due to application of electricalcurrent.

In some cases, it may be desirable to administer in the form of a kit,it may comprise a container for containing the separate compositionssuch as a divided bottle or a divided foil packet. Typically the kitcomprises directions for the administration of the separate components.The kit form is particularly advantageous when the separate componentsare preferably administered in different dosage forms (e.g., oral andparenteral), are administered at different dosage intervals, or whentitration of the individual components of the combination is desired bythe prescribing physician.

An example of such a kit is a so-called blister pack. Blister packs arewell known in the packaging industry and are widely used for thepackaging of pharmaceutical unit dosage forms (tablets, capsules, andthe like). Blister packs generally consist of a sheet of relativelystiff material covered with a foil of a plastic material that may betransparent.

Methods and compositions for the treatment of irritable bowel syndrome.Among other things, herein is provided a method of treating irritablebowel syndrome, comprising administering to a patient in need thereof atherapeutically effective amount of compound of Formula I:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

Wherein,

R¹, R³, R⁵ each independently represents H, D, CH₃CO—, CH₃, CD₃CO—,NULL,

R², R⁴, R⁶ each independently represents

n is independently 1, 2, 3, 4 or 5;a is independently 2, 3 or 7;each b is independently 3, 5 or 6;e is independently 1, 2 or 6;c and d are each independently H, D, —OH, —OD, C₁-C₆-alkyl, —NH₂ or—COCH₃.

Methods and compositions for the treatment of irritable bowel syndrome.Among other things, herein is provided a method of treating irritablebowel syndrome, comprising administering to a patient in need thereof atherapeutically effective amount of compound of Formula II:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof;

Wherein,

R¹, R³ each independently represents H, D, CH₃CO—, CH₃, CD₃CO—, NULL,

R², R⁴ each independently represents D, OD,

n is independently 1, 2, 3, 4 or 5;a is independently 2, 3 or 7;each b is independently 3, 5 or 6;e is independently 1, 2 or 6;c and d are each independently H, D, —OH, —OD, C₁-C₆-alkyl, —NH₂ or—COCH₃;within the proviso that there is

Each i independently represents

Methods of Making

Examples of synthetic pathways useful for making compounds of formula Iand formula II are set forth in example below and generalized in scheme1, scheme 2 and scheme 3, respectively:

Scheme-1 Synthesis of 1-(octanoyloxy)ethyl2-(dodecanoyloxy)-5-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamido)benzoate(CLX-SYN-G3-004)

Synthesis of Compound 2[(5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenoic acid]

Procedure:

(5Z,8Z,11Z,14Z,17Z)-ethyl icosa-5,8,11,14,17-pentaenoate (1, 50 g, 0.151mol) was dissolved in Methanol (1000 ml) and added NaOH aqueous solution(60.5 g, 1.513 moles, 200 ml of H₂O). Then the Reaction Mixture wasstirred for 2 h at room temperature. After completion of the reaction,volatiles were evaporated under reduced pressure on rotavap. Theobtained crude material was diluted with water (200 ml) and acidifiedwith 3N HCl, extracted with ethyl acetate (2×300 ml). The combinedorganic extracts were washed with brine (2×100 mL), dried over anhydroussodium sulfate, filtered and concentrated to dryness. Purification onsilica gel (20% EtOAc in hexane) gave compound 2 (38 g, 83.12% yield);Mass (m/z): 301 (M−H).

Step-2 Synthesis of (5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenoylchloride (3)

Procedure:

To a solution of compound 2 (10 g, 0.033 mol) in DCM (40 ml) was addedoxallyl chloride (4.32 ml, 0.049 mol) at 0° C., added 1 drop of DMF.Then the reaction mixture was stirred for 1 h at room temperature. Aftercompletion of the reaction, mixture was concentrated under N₂atmosphere. The obtained crude 3 (10 g) was taken up in the next stepwithout any further purification.

Step-3 Synthesis of Compound 5[2-hydroxy-5-(5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamidobenzoicacid]

Procedure:

To a solution of 5-amino-2-hydroxybenzoic acid (4, 5.06 g, 0.033 mol) inCH₂Cl₂ (20 ml) was added Triethyl amine (13.8 ml, 0.099 mol) andcompound 3 at 0° C. The mixture was continued to stir for 1 h at thesame temperature. After completion of the reaction, acidified with 2NHCl and separated the organic layer, dried over anhydrous sodiumsulfate, filtered and concentrated to dryness. Purification byrecrystallization in hexane gave compound 5 (5 g, 34.7% yield); Mass(m/z): 438.5 (M+H).

Step-4 Synthesis of Compound-6 [1-iodoethyl octanoate]

Procedure: Part-A:

To a stirred solution of Octanoic acid (10 g, 0.069 mol) indichloromethane (60 mL), 1-2 drops of DMF followed by oxallyl chloride(9.0 mL, 0.103 mol, 1.5 eq.) were added drop wise at 0° C. under N₂atmosphere for 20 min and stirred at room temperature. After beingstirred for 2 h volatiles were concentrated under nitrogen atmosphere togave octonoyl chloride [crude].

Part-B:

To a stirred solution of sodium iodide (10.3 g, 0.069 mol, 1 eq.) inacetonitrile (70 mL) at 0° C. was added acetaldehyde (3.88 ml, 0.069mol) then added the above acid chloride [Part-A] to it and stirred themixture for another 2 h at 0-5° C. After completion of the reaction(monitored by TLC) mixture was poured in to ice water (100 mL) andextracted with hexane (2×200 mL). The combined organic extracts werewashed with 5% aqueous sodiumthiosulfate solution (2×50 ml), 5% sodiumbicarbonate solution (50 mL) and finally with brine solution (2×50 ml),dried over anhydrous sodium sulfate, filtered and concentrated todryness to afford crude compound-6 as oil (10 g, 48.5%). Used in thenext step without any further purification.

Step-5 Synthesis of 1-(octanoyloxy)ethyl2-hydroxy-5-(5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamidobenzoate(CLX-SYN-G3-C03)

Procedure:

To a stirred solution of compound 5 (5 g, 0.011 mol, 1 eq.) in ethylacetate (110 mL) was added triethylamine (1.98 mL, 0.0133 mol, 2 eq.)drop wise at room temperature under N₂ atmosphere for 2 min, followed bysodium iodide (0.342 g, 0.002 mol) and compound-6 (5.09 g, 0.011 mol).Then reaction mixture temperature was raised to 50° C. and continued tostir it for overnight. After completion of the reaction (monitored byTLC) it was diluted with ethyl acetate and water. The organic layer wasseparated and dried over anhydrous sodium sulfate, filtered andconcentrated to dryness. Purification on silica gel (10% EtOAc inhexane) gave compound 1 (5.2 g, 75.3% yield with 98.18% purity by LC-MS)as a light yellow liquid. ¹H-NMR (CDCl3): δ 10.4 (s, 1H), 8.00 (S, 1H),7.50 (d, 1H), 7.18-7.05 (m, 2H), 6.88 (d, 1H), 5.40 (m, 10H), 2.82 (m,8H), 2.38 (m, 4H), 2.20 (m, 2H), 2.10 (m, 2H), 1.82 (m, 2H), 1.40-1.20(m, 12H), 1.00 (t, 3H), 0.9 (m, 6H); Mass: 608.5 [M+H].

Step-6 Synthesis of 1-(octanoyloxy)ethyl2-(dodecanoyloxy)-5-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamido)benzoate(CLX-SYN-G3-004)

To a solution of dodecanoic acid (3.30 g, 16.45 mmol) in DCM (100 mL) at0° C., oxalyl chloride (2.12 mL, 1.5 eq) was added along with a drop ofDMF. After stirring at room temperature for 1 h, the reaction mixturewas concentrated under nitrogen atmosphere and the crude was added to asolution of 1-(octanoyloxy)ethyl2-hydroxy-5-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamido)benzoate;compound 1 (10 g, 16.45 mmol, 1 eq), triethylamine (6.49 mL, 3 eq) inDCM (100 mL) at 0° C. The mixture was stirred at room temperature for 1h. After TLC showed completion of reaction, the mixture was acidifiedwith 2N HCl (40 mL). The organic layer was separated and dried overanhydrous sodium sulfate and concentrated. The crude was purified byflash chromatography (silicagel) and eluted with 20% EtOAC in hexane.The resulting product was further purified by prep-HPLC to obtain1-(octanoyloxy)ethyl2-(dodecanoyloxy)-5-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamido)benzoate(3.32 g, 25.54%) as brown liquid.

¹H-NMR (400 MHz, DMSO-d6): δ 10.16 (s, 1H), 8.15 (s, 1H), 7.90 (d, J=8.4Hz, 1H), 7.14 (d, J=8.4 Hz, 1H), 6.92 (m, 1H), 5.35 (m, 10H), 2.79-2.74(m, 8H), 2.56-2.49 (m, 4H), 2.32 (m, 4H), 2.09 (m, 2H), 1.99 (m, 2H),1.65 (m, 4H), 1.53 (m, 2H), 1.49 (d, J=5.2 Hz, 3H), 1.35 (m, 2H), 1.24(m, 20H), 0.90 (t, J=7.6 Hz, 3H), 0.83 (m, 6H); HPLC purity: 98.70%,Mass: 788.5 [M−H].

Scheme-2 Synthesis of 1-(octanoyloxy)ethyl5-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamido)-2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenoyl)oxy)benzoate(CLX-SYN-G3-005)

To a solution of (5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenoic acid(4.98 g, 16.45 mmol) in DCM (100 mL) at 0° C., oxalyl chloride (2.12 mL,1.5 eq) was added along with a drop of DMF. After stirring at roomtemperature for 1 h, the reaction mixture was concentrated undernitrogen atmosphere and the crude was added to a solution of1-(octanoyloxy)ethyl2-hydroxy-5-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamido)benzoate, compound 1 (10 g, 16.45 mmol, 1 eq), triethylamine (6.49 mL, 3eq) in DCM (100 mL) at 0° C. The mixture was stirred at room temperaturefor 1 h. After TLC showed completion of reaction, the mixture wasacidified with 2N HCl (40 mL). The organic layer was separated and driedover anhydrous sodium sulfate and concentrated. The crude was purifiedby flash chromatography (silicagel) and eluted with 20% EtOAC in hexane.The resulting product was further purified by prep-HPLC to obtain1-(octanoyloxy)ethyl5-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamido)-2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenoyl)oxy)benzoate(2.85 g, 19.41%) as dark brown liquid.

¹H-NMR (400 MHz, DMSO-d6): δ 10.16 (s, 1H), 8.15 (s, 1H), 7.90 (d, J=8.4Hz, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.92 (m, 1H), 5.39-5.25 (m, 20H), 2.81(m, 14H), 2.55 (t, J=7.6 Hz, 2H), 2.32 (m, 4H), 2.15-1.98 (m, 8H), 1.67(m, 4H), 1.51 (m, 2H), 1.48 (d, J=5.2 Hz, 3H), 1.22 (m, 10H), 0.90 (t,J=6.8 Hz, 6H), 0.83 (m, 3H); Mass: 890.6 [M−H].

Step-1: Synthesis of (5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenoicacid

(5Z,8Z,11Z,14Z,17Z)-ethyl icosa-5,8,11,14,17-pentaenoate 100.0 g (0.30mole, 1.0 eq) was dissolved in Methanol (2000 ml) and added NaOH aqueoussolution (Sodium hydroxide 121.0 g (3.02 mole, 10.0 eq) in Water 400 mL,4.0V). Then the Reaction Mixture was stirred for 4 h at roomtemperature. After completion of the reaction, volatiles were evaporatedunder reduced pressure till 4.0V reaction mass remain. The obtainedcrude material was acidified with 3N HCl to get the pH 1. Aqueous layerwas extracted with ethyl acetate (4×300 ml). The combined organicextracts were washed with brine (2×200 ml) and dried over anhydroussodium sulfate, filtered and concentrated to dryness. Obtained syrup wasused for next reaction. Yield: 80.0 g (87.4%), Purity: 97-99%

Step-2: Synthesis of (5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenoylchloride

To a solution of (5Z,8Z,11Z,14Z,17Z)-5,8,11,14,17-icosapentaenoic acid100.0 g (0.33 mole, 1.0 eq) and Dimethyl formamide 2.0 mL (0.02V) in DCM(400 ml, 4.0V) was added Oxalyl chloride 42.4 mL (0.49 mole, 1.5 eq) at0° C. Then the reaction mixture was stirred for 2 h at room temperature.After completion of the reaction, mixture was concentrated undernitrogen atmosphere. The obtained(5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenoyl chloride was taken upin the next step without any further purification. Yield: 106.0 g(100.0%).

Step-3: Synthesis of2-hydroxy-5-(5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamidobenzoicAcid

To a solution of 5-Amino Salicylic Acid 100.0 g (0.653 mole, 1.0 eq) inDichloromethane 800.0 mL (8.0V), Triethyl amine 91.0 mL (0.653 mole, 1.0eq) was added at 25° C.(5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenoyl chloride 209.5 g(0.653 mole, 1.0 eq) was dissolved in Dichloromethane 200.0 mL (2.0 V)and resultant solution was added to the above reaction mass at 0° C. Thereaction mass was stirred for 2 h at 25° C. After completion of thereaction, reaction mass was concentrated and dissolved in methanol(1500.0 ml) and cooled to 10-15° C. Aqueous solution of sodium hydroxide(600.0 ml) was added and reaction mass was stirred for 2 h at 25° C.After reaction completion, it was acidified with 2N HCl and extractedwith ethyl acetate, ethyl acetate layer was dried over anhydrous sodiumsulfate, filtered and concentrated to dryness. Purification byrecrystallization in n-heptane gave2-hydroxy-5-(5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamidobenzoicacid. Yield: 185.25 g (65.0%).

Step-4: Synthesis of Octanoyl Chloride

To a solution of Octanoic acid 100.0 g (0.693 mole, 1.0 eq) and Dimethylformamide 2.0 mL (0.02V) in Dichloromethane 600.0 mL (6.0V) was addedOxalyl chloride 90.0 mL (1.049 mole, 1.5 eq) at 0° C. Then the reactionmixture was stirred for 2 h at room temperature. After completion of thereaction, mixture was concentrated under nitrogen atmosphere. Theobtained (5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenoyl chloride wastaken up in the next step without any further purification. Yield: 112.8g (100.0%).

Step-5: Synthesis of5-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamido)-2-(octanoyloxy)benzoicacid

To a solution of2-hydroxy-5-(5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamidobenzoicacid 3.0 g (0.007 mole, 1.0 eq) in Ethyl acetate 30.0 mL (10.0V),Triethyl amine 1.8 mL (0.012 mole, 1.9 eq) was added at 25° C. Octanoylchloride 1.33 g (0.008 mole, 1.2 eq) was added slowly at 0° C. Thereaction mass was stirred for 16 h at 25° C. After completion of thereaction, reaction mass was concentrated and purified by columnchromatography using 0-2% Methanol in dichloromethane. Yield: 2.1 g(54.0%).

EQUIVALENTS

The present disclosure provides among other things compositions andmethods for treating irritable bowel syndrome (IBS) and theircomplications. While specific embodiments of the subject disclosure havebeen discussed, the above specification is illustrative and notrestrictive. Many variations of the systems and methods herein willbecome apparent to those skilled in the art upon review of thisspecification. The full scope of the claimed systems and methods shouldbe determined by reference to the claims, along with their full scope ofequivalents, and the specification, along with such variations.

INCORPORATION BY REFERENCE

All publications and patents mentioned herein, including those itemslisted above, are hereby incorporated by reference in their entirety asif each individual publication or patent was specifically andindividually indicated to be incorporated by reference. In case ofconflict, the present application, including any definitions herein,will control.

1. A compound of Formula I:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof; Wherein, R¹, R³, R⁵ eachindependently represents H, D, CH₃CO—, CH₃, CD₃CO—, NULL,

R², R⁴, R⁶ each independently represents

n is independently 1, 2, 3, 4 or 5; a is independently 2, 3 or 7; each bis independently 3, 5 or 6; e is independently 1, 2 or 6; c and d areeach independently H, D, —OH, —OD, C₁-C₆-alkyl, —NH₂ or —COCH₃.
 2. Acompound of Formula II:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,enantiomers, and stereoisomers thereof; Wherein, R¹, R³ eachindependently represents H, D, CH₃CO—, CH₃, CD₃CO—, NULL,

R², R⁴ each independently represents D, OD,

n is independently 1, 2, 3, 4 or 5; a is independently 2, 3 or 7; each bis independently 3, 5 or 6; e is independently 1, 2 or 6; c and d areeach independently H, D, —OH, —OD, C₁-C₆-alkyl, —NH₂ or —COCH₃; withinthe proviso that there is

Each i independently represents


3. A Pharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 4. A Pharmaceutical compositioncomprising a compound of claim 2 and a pharmaceutically acceptablecarrier.
 5. The pharmaceutical composition of claim 3, which isformulated to treat the underlying etiology with an effective amountadministering the patient in need by oral administration, delayedrelease or sustained release, transmucosal, syrup, topical, parenteraladministration, injection, subdermal, oral solution, rectaladministration, buccal administration or transdermal administration. 6.The pharmaceutical composition of claim 4, which is formulated to treatthe underlying etiology with an effective amount administering thepatient in need by oral administration, delayed release or sustainedrelease, transmucosal, syrup, topical, parenteral administration,injection, subdermal, oral solution, rectal administration, buccaladministration or transdermal administration.
 7. Compounds andcompositions of claim 5 are formulated for the treatment of underlyingetiology such as inflammatory bowel disease, crohn's disease, irritablebowel syndrome, coeliac disease, fructose malabsorption, mildinfections, parasitic infections like giardiasis, bile acidmalabsorption, functional chronic constipation, small intestinalbacterial overgrowth, and chronic functional abdominal pain. 8.Compounds and compositions of claim 6 are formulated for the treatmentof underlying etiology such as inflammatory bowel disease, crohn'sdisease, irritable bowel syndrome, coeliac disease, fructosemalabsorption, mild infections, parasitic infections like giardiasis,bile acid malabsorption, functional chronic constipation, smallintestinal bacterial overgrowth, and chronic functional abdominal pain.9. A method of treating at least one of an intestinal, an immunemediated disease and an inflammatory disease comprising: administeringthe compound of Formula I to patient suffering from at least one of aintestinal, an immune mediated disease and an inflammatory diseasecomprising

1-(octanoyloxy)ethyl2-(dodecanoyloxy)-5-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamido)benzoate.10. A method of treating at least one of an intestinal, an immunemediated disease and an inflammatory disease comprising: administeringthe compound of Formula I to patient suffering from at least one of aintestinal, an immune mediated disease and an inflammatory diseasecomprising

1-(octanoyloxy)ethyl5-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamido)-2-(((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenoyl)oxy)benzoate.